Hepatitis C: Beyond the Basics (FL INITIAL Autonomous Practice - Differential Diagnosis)

The primary mode of transmission of hepatitis C is by exposure to infected blood, and in the United States, injection drug use and the sharing of injection equipment is the most common way that hepatitis C is transmitted (CDC, 2019).

Transmission of hepatitis C by IV drug use is very efficient (Kim, 2019). It has been estimated that within one year of beginning IV drug use, one-third of all users will be infected, and the lifetime prevalence of hepatitis C infection in this population has consistently been found to be > 50% and often much higher (Kim, 2019). A study published in 2017 reported that in the United States, the prevalence of hepatitis C infection in people who inject drugs was 38.1%-68.0% (Degenhardt et al., 2017). Hepatitis C is more easily transmitted by IV drug use than is HIV, and recent increases in the incidence of hepatitis C infection have been directly linked to IV drug use and the opioid epidemic (Gonzalez & Trotter, 2018).,The risk of hepatitis C transmission and infection from a needle stick injury or other healthcare occupational exposure appears to be quite low (Naggie et al., 2017). Naggie et al. (2017) reviewed 12 studies (1992 to 2012) that described 3,929 healthcare occupational exposures to hepatitis C (Naggie et al., 2017). Most of the cases were needlestick injuries, and the transmission rate of hepatitis C was 0-10%. In three of the studies, there were no incidents of hepatitis C transmission, and in 11 of the 12, the rate of transmission was in the single digits (Degenhardt et al., 2017). Egro et al. (2017) retrospectively reviewed 1,361 healthcare exposures to hepatitis C contaminated blood (72.7%) or other body fluid (Ergo et al., 2017). There were 885 percutaneous and 476 mucous membrane exposures, and two employees were seroconverted, with a transmission rate of 0.1% (Ergo et al., 2017).

The risk of hepatitis C transmission from a blood transfusion has been estimated to be 1 case per 2 million units of transfused blood (CDC, 2019).

Hepatitis C can be transmitted by exposure to contaminated blood during tattooing, body piercing, and dental and medical procedures (CDC, 2019). The level of risk for hepatitis C transmission during hemodialysis is not known. Before 2006, the seroconversion rate in hemodialysis patients was 0.34% to 0.97% (Nguyen et al., 2019). From 2008 to 2018, there were 22 outbreaks of hepatitis C in hemodialysis units that were reported to the Centers for Disease Control and Prevention (CDC) and 104 patients who became infected (CDC, 2019). All of the outbreaks were caused by failure to adhere to standard precautions and infection control techniques (CDC, 2019).

Horizontal, non-sexual transmission of hepatitis C can happen, perhaps when blood-contaminated personal care items like nail clippers or razors are shared (Indolfi et al., 2019). However, since hepatitis C has been isolated in other body fluids and can survive in the environment outside of a host, determine how and how often this type of transmission occurs (Indolfi et al., 2019).

Hepatitis C has been found in cervical secretions, menstrual blood, semen, and vaginal secretions, but sexual transmission of hepatitis C between monogamous heterosexual partners who are not IV drug users appears to be very uncommon (Terrault et al., 2016). Terrault et al. (2013) reported that in monogamous heterosexual adults who were not IV drug users - and of whom 83% reported that they did not use condoms - the incidence of sexual transmission of hepatitis C was 0.07% per year or approximately one transmission of the virus per 190,000 sexual contacts (Terrault et al., 2016).

The risk of sexual transmission of hepatitis C is increased for people with multiple sex partners or sexually transmitted infections (Dienstag, 2020).

The incidence of hepatitis C in men who have sex with men (MSM) has been three times that of the general population, and hepatitis C is a commonly occurring disease in MSM who are not coinfected with HIV (Martin et al., 2018). Infection with HIV, ulcerative sexually transmitted diseases, and sexual behaviors that increase the risk for hepatitis C transmission are the likely causes of this difference (Martin et al., 2018).

Mother to child transmission of hepatitis C occurs in 3%-15% of all pregnancies, and 3% to 5% of the infections will become chronic (Ma et al., 2019). The risk of mother-to-child transmission increases if the mother is infected with HIV (Ma et al., 2019). Each year there are approximately 10,000-20,000 births to mothers infected with hepatitis C (Rossi et al., 2020).

Infectious levels of hepatitis C RNA have been detected in cerebrospinal fluid, saliva, sweat, tears, urine, and other body fluids (Pfaender et al., 2018). There are no documented cases of hepatitis C transmission after contact with these fluids; this may be because the fluids contain a relatively low viral load compared to blood (Naggie et al., 2017). However, the possibility of transmission after contact with these fluids cannot be ruled out (Pfaender et al., 2018).

The hepatitis C virus can survive and remain infectious on environmental surfaces for weeks, and it can survive and remain infectious in a syringe for weeks (Knight et al., 2018).

Hepatitis C is not transmitted by coughing, casual physical contact like holding hands or hugging, sharing eating or drinking utensils, or food or water.

The signs and symptoms of acute hepatitis C begin several weeks after exposure; the reported range of the time of onset is 2 to 26 weeks. Most patients who have an acute infection are asymptomatic, but 20%-30% will develop non-specific signs and symptoms like abdominal pain, anorexia, fatigue, fever, nausea, and vomiting; signs like jaundice that indicate liver damage can occur, as well. Serum aminotransferase levels can be very elevated, 10-20 times the upper limit of normal. However, the aminotransferase levels can also decrease, increase, and vary considerably during an acute hepatitis C infection, from very low to very high. Antibodies formed against the virus are usually detectable 8-11 weeks after infection. Hepatitis C RNA can be detected two weeks after infection (Ghany et al., 2019).

Clinical and biochemical recovery from an acute hepatitis C infection is usually complete within 3 to 6 months (Dienstag, 2020).

There are likely multiple causes or mechanisms by which a hepatitis C infection can be spontaneously cleared, including but not limited to:

1. Host factors like female gender, patients who have a chronic or resolved hepatitis B infection, variations in immune system response, specific genetic polymorphisms of the virus, and the patient's young age when first infected.
2. Viral factors, e.g., infection with genotype.
3. Other factors like a recent surgery or treatment of an HIV infection with highly active antiretroviral therapy (HAART) (Ghany et al., 2019).

Spontaneous clearance of the hepatitis C virus will not prevent reinfection with the same genotype or other genotypes.

A hepatitis infection that has not been spontaneously cleared by six months is considered chronic. Most patients with chronic hepatitis C infection, even those with fibrosis and cirrhosis, are asymptomatic (Ghany et al., 2019) The symptoms that do occur are non-specific or are caused by an extrahepatic complication (The latter will be discussed later), and serum transaminase levels in these patients are usually normal or mildly elevated (Dienstag, 2018). Cirrhosis develops in ~ 20% of patients, usually over 20-30 years; factors that increase the risk of developing cirrhosis are listed in Table 2.

Hepatic decompensation with ascites, bleeding, and encephalopathy32,36 is an uncommon complication of hepatitis C, occurring in ~ 4% of patients per year who have cirrhosis (Dienstag, 2018). Hepatocellular cancer occurs in ~ 1% of patients per year, and the risk for cancer is much higher for cirrhosis patients (Spearman et al., 2019).

The American Association for the Study of Liver Diseases (AASLD) and The Infectious Diseases Society of America (IDSA) state that screening for hepatitis C based only on the birth cohort (1945 to 1965) or on the presence of certain risk factors is inadequate (Ghany et al., 2019). The AASLD/ISDA recommendations for screening for hepatitis C are in Table 3 (Ghany et al., 2019).

Tests for hepatitis C are the anti-hepatitis C antibody test, measurement of hepatitis C RNA, and determining the hepatitis genotype.

Testing for hepatitis C begins with an anti-hepatitis C antibody test (Ghany et al., 2019). The test can be done using blood, a dried blood spot, plasma, serum, a finger stick, or oral fluids.

If the antibody test is negative, the patient does not have chronic hepatitis C, or the test result could be a false negative; a false negative can occur if the patient is infected with HIV, on hemodialysis, or is immunocompromised (Ghany et al., 2019). The antibody test can also be negative if the patient was recently exposed - within the past six months, anti-hepatitis C antibodies have not yet formed.

For patients who could have been exposed in the past six months, another antibody test can be done in 6 months, or a test for hepatitis C RNA can be done.

If the antibody and RNA tests are negative, the patient does not have hepatitis C (Ghany et al., 2019).

If the antibody test is positive but the RNA test is negative, the patient does not have acute or chronic hepatitis C infection. However, he/she could be reinfected (Ghany et al., 2019). In this situation, the positive antibody test likely represents a prior infection spontaneously cleared or cleared by drug therapy, but a false-positive antibody test can also occur (Singh et al., 2019). If it is suspected that the positive antibody tests are false positive, a different type of antibody test can be done (Ghany et al., 2019).

If the antibody test is positive and the RNA test is positive, the patient has hepatitis C.

There are at least six hepatitis C genotypes and dozens of subspecies.

Treatments that are effective against multiple genotypes are now available, but genotype testing is not needed unless the patient has been treated before and the virus was not cleared (Ghany et al., 2019).

Quantitative measurement of hepatitis C RNA, commonly called the viral load, should be done before drug therapy (Ghany et al., 2019).

Chronic hepatitis C infection causes inflammation of and damage to liver cells, resulting in hepatic fibrosis. Fibrosis is, essentially, the replacement of functional liver cells by scar tissue. Untreated fibrosis can be mild and reversible, but stage 3 bridging fibrosis and stage 4 fibrosis (the latter is also called cirrhosis) may not be reversible, and bridging fibrosis and cirrhosis are risk factors for liver decompensation and hepatocellular cancer. Note: Hepatic decompensation refers to the signs, symptoms and clinical conditions that can occur when liver damage is severe and hepatic function is compromised, e.g., ascites, bleeding, esophageal varices, and hepatic encephalopathy.

Accurately staging a patient's level of fibrosis and determining if she/he has cirrhosis identifies patients at risk for serious complications, and staging can predict outcomes. Liver fibrosis in patients infected with hepatitis C can be detected and evaluated with invasive or noninvasive techniques (Lai & Afdhal, 2019).

Liver biopsy was long considered the gold standard test for detecting liver fibrosis. However, liver biopsy is invasive. Pain, bleeding, and significant complications like punctured gall bladder and pneumothorax can occur, and the procedure is associated with a mortality rate of 0.33% (Lai & Afdhal, 2019). Also, the amount of tissue sampled and examined is very small, approximately 1/50,000 of the liver's mass. Thus sampling errors can occur, and there can be significant variability in intra and inter-observer assessment of the degree of fibrosis (Lai & Afdhal, 2019). The usefulness of liver biopsy is also limited because liver tissue is examined at one point, fibrosis is a dynamic, ongoing process, and repeating the liver biopsy is not practical (Bang et al., 2017). A liver biopsy may be needed if the results of noninvasive testing are equivocal or if the patient may have another liver disease (Ghany et al., 2019).

Noninvasive techniques for detecting and determining the degree of fibrosis are:

1. Blood tests that provide an indirect or direct measurement of fibrosis, and
2. Imaging tests

These are the preferred methods for detecting liver fibrosis and determining the level of fibrosis in patients who have hepatitis C.

Blood tests-indirect measurement: Indirect measurements of fibrosis use patient data, e.g., age and weight, and laboratory tests. The laboratory tests may be routine tests like measurements of albumin, AST and ALT, and platelets, or they may be measurements of enzymes, proteins, and other compounds like α2-macroglobulin, gamma-glutamyl transferase (GGT), and haptoglobin that are produced by the liver (Lai & Afdhal, 2019). In either case, the patient information and test results are combined to provide a score that reflects the degree of liver fibrosis. Examples of tests that provide an indirect measurement of fibrosis include the AST to platelet ratio (APRI), the non-alcoholic fatty liver disease (NAFLD) fibrosis score, FIB-4, ActiTest, Fibrosure, Fibro Test, and Hepascore (Lai & Afdhal, 2019).

Blood tests-direct measurement: Blood tests that provide a direct assessment of liver fibrosis combine measurement of compounds that are involved in the buildup and breakdown of the hepatic matrix, measurement of enzymes, measurement of cytokines and chemokines that are associated with fibrogenesis, and measurement of proteins and other compounds like α2-macroglobulin, gamma-glutamyl transferase (GGT), haptoglobin that is produced by the liver (Lai & Afdhal, 2019). Examples include FibroSpect II and the European Liver Fibrosis panel (ELF) (Curry & Afdhal, 2019).

Imaging tests: The primary imaging technique used to detect liver fibrosis in patients with hepatitis C is shear wave elastography (Curry & Afdhal, 2019). Shear wave elastography uses different modes of impulse formation that generate shear waves in the liver (Curry & Afdhal, 2019). Healthy liver tissue and fibrotic liver tissue respond to the shear waves in different ways, and shear wave elastography is a safe and accurate way of detecting and grading liver fibrosis in patients with hepatitis C (Curry & Afdhal, 2019). There are different ways in which shear waves can be generated. In the United States, the most commonly used method is vibration-controlled transient elastography (Lim et al., 2017). A hand-held probe is placed on the abdominal wall, and the shear waves are displayed on a monitor; the procedure takes little time to complete, and it can be done at the bedside or in an office.

Each indirect and direct blood test for detecting and evaluating fibrosis has advantages and disadvantages, e.g., specificity and positive predictive value, and none of the specific tests are universally considered part of the standard of care (Curry & Afdhal, 2019). As for imaging tests, the American Gastroenterology Association recommends using vibration-controlled transient elastography (Lim et al., 2017). However, their review (2017) did not compare this technique with other imaging techniques and other techniques, i.e., point shear wave elasticity (Point-SWE) and 2D-SWE have been found to compare favorably with transient elastography (Dietrich, 2020).

If a chronic hepatitis C infection has been confirmed and treatment is planned, the laboratory tests listed in Table 4 should be done (Ghany et al., 2019). The need for blood glucose, BUN, and creatinine will be explained in extrahepatic complications and drug therapy sections. Vitamin D deficiency may be a contributing cause of hepatitis C infection or a result of the infection, and vitamin D deficiency may cause hepatic damage in infected patients (Hoan et al., 2018).

Depression, fatigue, mood disorders, memory deficits and cognitive impairment are common in patients with chronic hepatitis C infection; for example, depression in people with hepatitis C is higher than in the general population (Yeoh et al., 2018). These cognitive and psychiatric complications can occur in infected patients who do not have liver dysfunction, and their cause is likely multi-factorial. A preexisting psychiatric illness may cause them, they may be an expected emotional and psychological consequence of having a chronic infection, and there is evidence that the hepatitis C virus itself and the inflammatory state caused by the infection can directly injure the brain and CNS (Yeoh et al., 2018). Viral clearance after treatment with direct-acting antiviral drugs has been shown to improve the psychological complications of the disease, but these cognitive and psychiatric problems may persist after a cure (Yeoh et al., 2018).

Chronic hepatitis C infection has been consistently associated with type 2 diabetes mellitus (DM) (Sevastianox et al., 2020). The prevalence of DM is higher in people infected with hepatitis C, and infection with hepatitis C may increase the risk of developing type 2 DM (Chen et al., 2019). especially in patients with risk factors for type 2 DM (Sevastianox et al., 2020). How and when hepatitis C causes or increases the risk for type 2 DM is unknown (Chopra & Flamm, 2019). Insulin resistance is quite common in hepatitis C infected patients - a prevalence as high as 62% has been reported (Wang et al., 2020). Insulin resistance can occur in infected patients who do not have significant fibrosis or cirrhosis (Stone, 2020).

Mixed cryoglobulinemia is one of the most common extrahepatic complications of hepatitis C infection. Mixed cryoglobulinemia is an immune system-mediated process that causes the formation of specific immunoglobulins called cryoglobulins (Stone, 2020). The cryoglobulins are deposited in small and medium-sized blood vessels (Stone, 2020). causing obstruction or vasculitis, arthralgia, skin disorders like necrotic ulcers and purpura, renal complications like glomerulonephritis, and neurologic complications like peripheral neuropathy (Chopra & Flamm, 2019). The skin, joints, kidneys, and peripheral nervous system are often affected, but cardiovascular, gastrointestinal, and pulmonary complications can occur (Galli et al., 2019).

Between 40-60% of patients with chronic hepatitis C infection have mixed cryoglobulinemia (Lee et al., 2019).

The prevalence of hepatitis C infection in patients with chronic kidney disease (CKD) and end-stage renal disease is very high, much higher than in the general population (Gordon et al., 2019). Hepatitis C infection has been associated with an increased CKD progression and morbidity and mortality in hemodialysis patients (Iliescu et al., 2020). Hepatitis C can also cause renal damage, usually by cryoglobulinemia or possibly by a direct effect on the kidneys (Gordon et al., 2019).

Hepatitis C is the leading cause of hepatocellular cancer in the United States, and hepatocellular cancer is an important cause of mortality in patients who have chronic hepatitis C infection (Park et al., 2019). Between 1%-4% of chronically infected patients will develop hepatocellular cancer, and the risk of hepatocellular cancer is much higher for patients with advanced fibrosis or cirrhosis (Kanwal et al., 2020).

Hepatitis C has also been proven to cause B-cell non-Hodgkin lymphomas, and hepatitis C has been associated with an increased risk of other cancers (Nyberg et al., 2019).

Coinfection with hepatitis C and HIV is common; estimates of the prevalence of coinfection range from 6.2% to 37% and 80% to 90% in people who are injection drug users (Sikavi et al., 2018).

An HIV infection in patients with chronic hepatitis C contributes to a poor prognosis. An HIV infection increases the replication of the hepatitis C virus, increases the progression of fibrosis, increases the risk of developing cirrhosis, and diminishes the response to the direct-acting antivirals (Falade-Nwulia, 2019). Coinfection with hepatitis C and HIV also increases the risk of developing hepatocellular cancer, and hepatitis C infection is a common cause of death in people who have an HIV infection (Chen et al., 2018).

Hepatitis C infection does not appear to affect the clinical course of HIV infection adversely (Chen et al., 2018).

The American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (ISDA) operate a website, HCV Guidance: Recommendations for Testing, Managing and Treating Hepatitis C (www.hcvguidelines.org/), and the website has basic clinical guidelines advice and hepatitis C treatment regimens.

The regimens differ depending on factors including (but not limited to) the presence or absence of cirrhosis, previous treatment for hepatitis C and the genotype and subspecies of the virus.

The AASLD/ISDA developed two simplified treatment plans for two specific patient populations (Ghany et al., 2019). These two treatment plans (listed below) and their drugs are discussed here; treatment plans for other clinical situations of hepatitis C infection can be viewed on the AASLD/ISDA website.

1. Patients with chronic hepatitis C infection, genotype 1-6, treatment naïve, and who do not have cirrhosis.
2. Patients with chronic hepatitis C infection, genotype 1-6, who are treatment naïve, and who have compensated cirrhosis.

These two plans should not be used in any of the clinical conditions/situations listed in Table 5 (Ghany et al., 2019). Specific treatment plans for these clinical conditions/situations are available, discussed later in this section.

The AASLD/ISDA website also developed regimens for many other patient populations, e.g., a patient with genotype 3 with decompensated cirrhosis who has previously been treated with interferon and ribavirin. All the recommended treatment regimens can be viewed on www.hcvguidelines.org/.

Two drug regimens are recommended, glecaprevir mg/pibrentasvir or sofosbuvir/velpatasvir. Either one can be used, and both effectively treat hepatitis genotypes 1-6 (Mavyret, 2020).

Before initiating treatment:

1. Calculate the FIB-4 score: The FIB-4 score uses the patient's age and measurement of platelet count, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) to estimate the degree of liver fibrosis (Ghany et al., 2019). The FIB-4 score is a reliable way to determine the presence and degree of liver fibrosis (Chen et al., 2019).
2. Determine the absence/presence of cirrhosis: A patient is presumed to have cirrhosis if the FIB-4 score is > 3 (Knight et al., 2018). Alternatively, if any of the following are present: Clinical evidence of cirrhosis, e.g., liver nodularity or splenomegaly is seen by an imaging study; a platelet count < 150,000 mm3; cirrhosis detected by liver biopsy; cirrhosis detected by transient elastography, or; a noninvasive serologic test result, e.g., a Fibrosure score, that is above the cut-off point for cirrhosis (Ghany et al., 2019).
3. Blood tests: Six months or less before starting treatment, these blood tests should be done: AST and ALT, CBC, eGFR, serum albumin, and total and direct bilirubin. Before starting treatment, measure the hepatitis C RNA level, check for HIV antibody and antigen and check for hepatitis B surface antigen (Ghany et al., 2019). Do a serum pregnancy test (Ghany et al., 2019).
4. Medication list: Determine what prescription and over-the-counter medications the patient is taking. Be sure to ask the patient if he/she is taking alternative medicine products, dietary supplements, or herbal products. Check for drug-drug interactions between the direct-acting antivirals that will be prescribed and the medications, supplements, etc., that the patient is taking.
   1. Patients who take medications to treat diabetes mellitus should be advised that the direct-acting antivirals used in these protocols can affect glucose metabolism (Ghany et al., 2019). Treatment with direct-acting antivirals can decrease insulin resistance, and in patients who have an SVR in response to treatment, fasting plasma glucose and glycated hemoglobin level, HbA1c, can be significantly reduced (Ciancio et al., 2018). Because of this, patients who continue taking the same doses of the same antidiabetic medications may develop symptomatic hypoglycemia (UpToDate, 2020).
   2. Concomitant use of direct-acting anticoagulants and warfarin decreases the effectiveness of warfarin and can cause a sub-therapeutic INR (Ghany et al., 2019).
5. Provide patient counseling: This will be discussed later in the module in the Patient Education section.

Glecaprevir/pibrentasvir is an NS3/4A protease inhibitor/NS5A protein inhibitor combination.

Dose: Three tablets taken once a day, with food, for eight weeks (Mavyret, 2020).

Dosing/geriatric: No dosing adjustments are needed (Mavyret, 2020).

Dosing/hepatic impairment: Mavyret can be used in patients who have compensated cirrhosis, Child-Pugh score A, and no dosing adjustment is required (Mavyret, 2020). See Contraindications and Warnings and precautions for other information about Mavyret and hepatic impairment patients.

Dosing/renal impairment: No dosing adjustments are needed.

Contraindications: Glecaprevir 300 mg/pibrentasvir should not be taken by patients for whom ribavirin is contraindicated (Mavyret, 2020).

Mavyret is contraindicated in patients with moderate to severe hepatic impairment, Child-Pugh score B or C and in patients who have evidence of previous episodes of hepatic decompensation (Mavyret, 2020).

US Boxed Warning: Hepatitis B virus reactivation has been reported in hepatitis C/hepatitis B coinfected patients who were undergoing or had completed treatment with hepatitis C direct-acting antivirals and were not receiving hepatitis B antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death (Mavyret, 2020).

Note: Treating patients who are infected with hepatitis B and C will be discussed later in the module.

Warnings and precautions: In August 2019, the FDA issued a safety warning about Mavyret and two other direct-acting antivirals (FDA, 2019).

"The Food and Drug Administration (FDA) has received reports that the use of Mavyret, Zepatier, or Vosevi to treat chronic hepatitis C in patients with moderate to severe liver impairment has resulted in rare cases of worsening liver function or liver failure. In most patients, symptoms resolved, or the worsening of liver function improved after stopping the medicine. In most cases, liver failure or decompensation typically occurred within the first four weeks of starting treatment (FDA, 2019)."

The safety warning notes that the majority of the patients who had severe outcomes had moderate or severe hepatic impairment (Child-Pugh B or C) before they took these drugs; some patients with mild hepatic impairment (Child-Pugh A) before antiviral therapy had had prior episodes of hepatic decompensation, and; there were rare cases of patients who did not have any degree of hepatic impairment but who had evidence of portal hypertension and who developed hepatic decompensation/liver failure (FDA, 2019). Also, some patients had risk factors for hepatic decompensation/liver failure like alcohol abuse or liver cancer (FDA, 2019).

The FDA recommended that healthcare professionals continue to use Mavyret, Zepatier, or Vosevi as indicated by the prescribing information, do a baseline assessment of liver function before starting antiviral therapy, and closely monitor patients for signs and symptoms of liver failure (Epclusa, 2020).

Adverse effects: During clinical trials, > 5% of patients had headache (13%), fatigue (11%) and nausea (8%) (Mavyret, 2020).

Drug interactions: The Lexicomp® Drug Interaction database lists 92 drug-drug interactions involving glecaprevir and pibrentasvir, and many of these involve commonly used drugs like antidiabetics antiepileptics, statin drugs, and warfarin.

Drug-drug interactions can be checked using the University of Liverpool drug interaction checker (Ghany et al., 2019). The website address is www.hep-druginteractions.org/checker. The AASLD/ISDA website has drug-drug interaction information, as well.

Monitoring: If there are no signs and symptoms of liver damage, there is no need to do laboratory testing during the treatment.

Twelve weeks or later, after the last dose, obtain a quantitative measurement of hepatitis C RNA and do a hepatic function panel: A hepatic panel should measure albumin, alkaline phosphatase, ALT, AST, and total direct bilirubin.

If SVR has been attained and the AST and ALT are normal, no further treatment or follow-up is needed (Ghany et al., 2019).

If an SVR has been attained, but the AST and ALT are elevated, the patient should be assessed for other causes of liver damage (Ghany et al., 2019).

If an SVR has not been attained, the patient should be referred to a specialist (Ghany et al., 2019).

Treatment failure will be discussed later in the module.

During clinical trials of glecaprevir/pibrentasvir, 99% of patients who had genotype 1 had an SVR. The SVR for the other genotypes was 98% (genotype 2), 93% (genotype 4), 95% (genotype 5), and 100% (genotype 6) (Mavyret, 2020). Patients who had genotype three were not included in these clinical trials.

Sofosbuvir/velpatasvir is an NS5A protein inhibitor/NS5B polymerase inhibitor.

The package insert for Epclusa, the brand name form of sofosbuvir/velpatasvir, recommends one dosing regimen for genotypes 1-6 in patients who are treatment naïve and who do not have cirrhosis or who have compensated cirrhosis (Epclusa, 2020).

However, the AASLD/ISDA algorithm states that drug resistance testing should be done if the patient has genotype (Ghany et al., 2019). If drug resistance testing reveals that the patient has a specific hepatitis C genetic polymorphism, the Y93H polymorphism, a lower SVR may occur, and the AASLD/ISDA recommends that the patient should be treated with sofosbuvir/velpatasvir and weight-based ribavirin or with another drug, e.g., sofosbuvir/velpatasvir/voxilaprevir (Ghany et al., 2019). Dosing: Once tablet, once a day, for 12 weeks (Epclusa, 2020).

Dosing/geriatric: No dosing adjustments are needed (Epclusa, 2020).

Hepatic impairment: Patients who have a mild, moderate, or severe hepatic impairment, Child-Pugh A, B, or C, no dosing adjustment needed (Epclusa, 2020).

Renal impairment: Patients who have mild, moderate, or severe renal impairment, including ESRD patients and require hemodialysis. No dosing adjustments are needed (Epclusa, 2020).

Contraindications: Epclusa is contraindicated in patients with ribavirin (Epclusa, 2020).

US Boxed Warning: Hepatitis B virus reactivation has been reported in hepatitis C and hepatitis B coinfected patients undergoing or had completed treatment with hepatitis C direct-acting antivirals and were not receiving hepatitis B antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death (Epclusa, 2020).

Warnings and precautions: Concurrent use of sofosbuvir/velpatasvir and amiodarone can cause serious, symptomatic bradycardia. This is especially likely if the patient is also taking a beta-blocker or if she/he has the cardiac disease or advanced liver disease (Epclusa, 2020).

P-glycoprotein (P-GP) is a transport protein, and one of its primary functions is to move xenobiotics out of cells. P-glycoprotein-inducing drugs like carbamazepine and phenytoin can lower the plasma level of sofosbuvir/velpatasvir and reduce its therapeutic effectiveness (Epclusa, 2020). Drugs that are moderate to strong inducers of CYP2B6, CYP2C8, and CYP3A4 can also have this effect (Epclusa, 2020).

Adverse effects: Adverse effects occurring in > 5% of patients are asthenia (lack of energy, weakness), fatigue, headache, insomnia, and nausea (FDA, 2019).

Drug interactions: The Lexicomp® Drug Interactions database lists 93 drug-drug interactions involving sofosbuvir/velpatasvir, and many involve commonly used medications like antidiabetic medications, e.g., glipizide and metformin, and warfarin (UpToDate, 2020b).

Drug-drug interactions can be checked using the University of Liverpool drug interaction checker (Ghany et al., 2019). The website address is www.hep-druginteractions.org/checker. The AASLD/ISDA website has drug-drug interaction information, as well.

Monitoring: If there are no signs and symptoms of liver damage, there is no need to do laboratory testing during the treatment.

Twelve weeks or later, after the last dose, obtain a quantitative measurement of hepatitis C RNA and do a hepatic function panel. If SVR has been attained and the AST and ALT are normal, no further treatment or follow-up is needed (Ghany et al., 2019).

If an SVR has been attained, but the AST and ALT are elevated, the patient should be assessed for other causes of liver damage (Ghany et al., 2019).

If an SVR has not been attained, the patient should be referred to a specialist (Ghany et al., 2019).

Treatment failure will be discussed later in the module.

During clinical trials, the SVR for all patients, with or without compensated cirrhosis, genotypes 1,2, 4,5, and 6, was 99%.

Perform the same pretreatment assessment as for patients without compensated cirrhosis, and in addition:

1. Calculate CTP score: If the Child-Turcotte-Pugh (CTP) score is ≥ 7, CTP-B or CTP-C, the patient has decompensated cirrhosis and should not be treated with these regimens. (Note: The CTP and the Child-Pugh are the same).
2. Do an ultrasound of the liver within six months or less of starting treatment; this is done to exclude the presence of hepatocellular cancer and subclinical ascites (Ghany et al., 2019).

Either glecaprevir 300 mg/pibrentasvir 120 mg, or sofosbuvir 100 mg/velpatasvir 100 mg can be used (Ghany et al., 2019).

It may be prudent to do laboratory testing for liver damage during treatment with these specific drugs. Some patients who have cirrhosis and take direct-acting antivirals can develop hepatic decompensation. If the patient has physical or laboratory evidence of liver damage, she/he should be referred to a specialist.

Twelve weeks or later, after the last dose, obtain a quantitative measurement of hepatitis C RNA and do a hepatic function panel. If SVR has been attained and the AST and ALT are normal, no further treatment or follow-up is needed (Ghany et al., 2019).

If an SVR has been attained, but the AST and ALT are elevated, the patient should be assessed for other causes of liver damage (Ghany et al., 2019).

If an SVR has not been attained, the patient should be referred to a specialist (Ghany et al., 2019).

The AASLD/ISDA simplified treatment guidelines state that if the patient is positive for hepatitis B surface antigen (Acutely or chronically infected), direct-acting antivirals are contraindicated (Ghany et al., 2019). The prescribing information of the direct-acting antivirals advises that the use of these drugs in patients who have or who had hepatitis B infection can cause worsening of hepatitis B (a flare) or a reactivation, i.e., loss of immune control, and increased hepatitis B viral replication, during and after drug therapy.

Hepatitis B flare or reactivation does occur during direct-acting antiviral therapy, primarily in patients who are hepatitis B surface antigen-positive but also in patients who have hepatitis B antibodies or who have an occult infection, i.e., hepatitis B surface antigen-negative but detectable hepatitis B DNA (Pisaturo et al., 2019). The risk for reactivation has been reported to be 2%-57%, but serious liver damage in these cases is rare (Pisaturo et al., 2019).

There is very little information about using direct-acting antivirals to treat chronic hepatitis C in patients who were or currently are infected with hepatitis B (Butt et al., 2020). Chopra et al. (2019) and Abdelaal et al. (2019) recommend that if treatment for chronic hepatitis is planned, patients who meet the criteria for treatment of hepatitis B should be treated, either before or during the hepatitis C treatment (Abdelaal et al., 2019). The AASLD/ISDA website states that for patients who are on direct-acting antiviral therapy, who are hepatitis B surface antigen-positive but are not going to be treated because the hepatitis B DNA level is low, one of two approaches can be used:

1. Monitor the hepatitis B DNA level once a month during and after direct-acting antiviral treatment. (Note: It is not mentioned how long after drug therapy has finished, the monitoring should be continued) If the level increases by 10-fold above the baseline or becomes > 1000 IU/mL, start hepatitis B antiviral therapy.
2. Start hepatitis B antiviral therapy and continue it for 12 weeks after the last dose of direct-acting antiviral treatment.

The rate of adverse effects and the efficacy of the direct-acting antivirals are similar in patients infected with hepatitis C and HIV and patients infected only with hepatitis C. The direct-acting antiviral treatment protocols for coinfected patients are no different (AASLDS, 2020). However, many potentially serious drug-drug interactions exist between the direct-acting antivirals and the antiretroviral drugs used to treat HIV infection (AASLDS, 2020). The AASLD/ISDA recommends that clinicians consult a drug interaction database when planning to treat patients for hepatitis C and HIV, and for this purpose, the AASLD/ISDA website mentions two drug interaction resources (AASLDS, 2020).

1. The University of Liverpool drug interactions website, www.hep-druginteractions.org/.
2. The US Department of Health and Human Services HIV treatment guidelines aidsinfo.nih.gov/guidelines

Pregnant women should be tested for hepatitis C (AASLDS, 2020b).

Treatment with direct-acting antivirals is beneficial for the health of hepatitis C infected women of reproductive age, and it can eliminate the risk of mother to child transmission of the virus (AASLDS, 2020b). Infected women should be advised to delay pregnancy until after treatment has ended and an SVR has been attained (AASLDS, 2020b).

Treating hepatitis C infected women who are pregnant is problematic. The prescribing information for these drugs states that no adequate human data are available to establish if the direct-acting antivirals have an adverse effect on pregnancy outcome, and the AASLD/ISDA website states . . . there are no available data on the use of pangenotypic regimens during pregnancy" (AASLDS, 2020b).

The AASLD/ISDA recommends that direct-acting antiviral therapy be considered (Italics added) for pregnant women on a case by case basis after the patient has been informed about the benefits and risks (AASLDS, 2020b). While taking direct-acting antivirals, women who become pregnant should consult with a healthcare practitioner about the benefits and risks of continuing treatment (AASLDS, 2020b).

Ribavirin is contraindicated for pregnant women (AASLDS, 2020b).

Elective cesarean delivery is not recommended (AASLDS, 2020b).

During perinatal care and delivery, diagnostic testing should be done by amniocentesis, not chorionic villus sampling, and episiotomies, internal fetal monitoring, and prolonged membrane rupture should be avoided (AASLDS, 2020b).

Hepatitis C infection is not a contraindication for breastfeeding unless the woman's nipples are bleeding, cracked, or damaged (AASLDS, 2020b). The direct-acting antivirals have not been studied in nursing women.

Direct-acting antiviral therapy can improve the clinical status of patients who have hepatitis C and decompensated cirrhosis, but the response rate, i.e., the SVR, is lower than for patients without cirrhosis (AASLDS, 2020c).

The ASSLD/ISDA recommendations for patients who have decompensated cirrhosis, genotype 1-6, who can take ribavirin, and are treatment naïve are (AASLDS, 2020c):

1. Genotype 1,4,5, or 6 only: Ledipasvir 90 mg/sofosbuvir 400 mg and a low initial dose of ribavirin, 600 mg. The ribavirin dose can be increased to a weight-based dose as tolerated. Once a day dosing, 12 weeks duration.
2. Sofosbuvir 400 mg/velpatasvir 100 mg with a weight-based dose of ribavirin. Once a day dosing, 12 weeks duration.

If the patient has a Child-Pugh score of C, i.e., severe hepatic impairment, a low initial 600 mg dose of ribavirin is recommended, and the dose can be increased to a weight-based dose as tolerated.

The ASSLD/ISDA recommendations for patients who have decompensated cirrhosis, genotype 1-6, who cannot ribavirin, and are treatment naïve are (AASLDS, 2020c):

1. Genotype 1,4,5, or 6 only: Ledipasvir 90 mg/sofosbuvir 400 mg. Once a day dosing, 24 weeks duration.
2. Sofosbuvir 400 mg/velpatasvir 100 mg. Once a day dosing, 24 weeks duration.

Elbasvir/grazoprevir, glecaprevir/pibrentasvir, and sofosbuvir-based regimens have been successful in treating patients who have severe renal impairment and patients who have ESRD and require hemodialysis (AASLDS, 2019). These direct-acting antivirals improve mortality rates, reduce the risk of developing extrahepatic complications, and they are well tolerated and appear to be safe for this patient population (AASLDS, 2019).

No dosing adjustments of the direct-acting antivirals are required, but if the patient has CKD stage 3, 4, or 5, a dosing adjustment of ribavirin may be needed (AASLDS, 2019).

Direct-acting antiviral therapy has been shown to reduce the risk of developing hepatocellular cancer (AASLDS, 2019b). However, in treatment naïve infected patients who have hepatocellular cancer, there is a small but statistically significant decrease in the SVR attained by direct-acting antivirals (AASLDS, 2019b). Also, the American Gastroenterological Association (AGA) expert review on direct-acting antivirals and hepatocellular cancer stated:

1. "There is no conclusive data that DAA therapy is associated with increased or decreased risk, differential time to recurrence, or aggressiveness of recurrent HCC in patients with complete response to HCC therapy. Although data have demonstrated a decreased risk of incident HCC after DAA therapy in patients with HCV cirrhosis, there continues to be debate about the risk and aggressiveness of HCC recurrence after DAA therapy in patients with a history of HCC" (AASLDS, 2019b).
2. Clinicians and patients must consider the possibility of recurrent hepatocellular cancer versus the long-term benefits of direct-acting antiviral therapy. The AGA believes that for most patients, the benefits outweigh the risks (AASLDS, 2019b).
3. The shorter the interval between successful response to treatment of hepatocellular cancer and initiation of treatment of hepatitis C, the greater the risk that cancer will recur. The AGA believes that it is prudent to wait for at least 4 to 6 months after the successful treatment of hepatocellular cancer before starting antiviral therapy (AASLDS, 2019b).

The AASLD/ISDA recommends measuring hepatitis C RNA 12 weeks or later after the directing acting antiviral treatment has been completed. Less than 1% of patients will relapse after the 12-week point, and some of these cases may be reinfection (Chopra, 2018). A relapse 24 weeks after the end of treatment is very rare (Terrault, 2018).

If an SVR has been attained and the patient does not have cirrhosis, no further assessment for hepatitis C infection or liver damage is needed unless the patient has signs/symptoms of liver damage or if reinfection occurs or might have occurred (AASLDS, 2020d).

If an SVR has been attained and the patient has cirrhosis, the patient should be screened for hepatocellular cancer, and the AASLD recommends an ultrasound examination, with or without alpha-fetoprotein testing, every six months (AASLDS, 2020d). Also, the AASLD recommends that an endoscopic examination for the detection of esophageal varices be periodically done (AASLDS, 2020d).

Treatment failures are caused by viral and host issues like drug-resistant viral sub-species, immune system factors, comorbidities, and lifestyle (Daniel et al., 2020).

Patients who did not respond to direct-acting antiviral therapy can develop fibrosis, if they have fibrosis, it may worsen, and they can transmit the virus (AASLDS, 2020d).

A patient who did not attain an SVR should be reevaluated by a specialist and considered for retreatment. The AASLD/ISDA website has treatment recommendations for patients who had a treatment failure. In these patients, the AASLD recommends an ultrasound examination, with or without alpha-fetoprotein testing, every six months, and periodic endoscopic examination for the detection of esophageal varices should be periodically done, as well (AASLDS, 2020d). Also, a CBC, hepatic function panel and an INR should be done every 6 to 12 months (AASLDS, 2020d).

A cure does not provide immunity against infection from the same genotype or other genotypes, and reinfection can occur. Injection drug users, MSM infected with HIV, and MSM taking pre-exposure HIV prophylaxis have a relatively high risk of reinfection (AASLDS, 2020d). These patients and anyone else at risk for reinfection should be screened annually for hepatitis C (Ghany et al., 2019).

Transmission of the virus: Patients should be instructed not to share personal care items like toothbrushes and razors that may be contaminated with blood.

Sexual transmission of hepatitis C between monogamous heterosexual partners who are not IV drug users appears very uncommon. The CDC does not have a recommendation about the use of barrier protection in this patient population. The AASLD/ISDA states that since patients who are infected with hepatitis C are more likely to have hepatitis B or HIV, both of which are sexually transmitted, the use of barrier protection should at least be considered, even for people in a stable, monogamous relationship (AASLDS, 2020d). Patients should be counseled on safe sex practices, and they should be given information on how hepatitis C is transmitted and instructed on how to avoid transmission of the virus.

People who have multiple sexual partners and MSM should be encouraged to use condoms (Ghany et al., 2019).

Injection drug users should be advised not to share needles or injection drug equipment.

Hepatitis C is not transmitted by casual physical contact, coughing, food or water, sneezing, or sharing eating utensils.

Alcohol: There is no amount of alcohol that has been established as safe for patients who have hepatitis C (Ghany et al., 2019). Excess alcohol consumption can cause cirrhosis, and it has been strongly associated with the development and progression of fibrosis and with hepatocellular cancer (AASLDS, 2019b). Patients should be advised to abstain from drinking alcohol and patients who have an alcohol use disorder should be referred for treatment (AASLDS, 2019b).

Drug-drug interactions: Patients should be told that drug-drug interactions can negatively influence the effectiveness of direct-acting antivirals, and potentially significant interactions can occur between over-the-counter medications and dietary/herbal supplements and the direct-acting antivirals. Do not take a new medication or supplement without informing the provider or another healthcare professional.

Patients who take antidiabetic medications or warfarin should be instructed that the antiviral medications may cause hypoglycemia and can reduce the anticoagulant effects of warfarin.

Employment: People who have hepatitis C should not be restricted from employment. Infected healthcare workers must simply follow infection control procedures and use Standard Precautions.

Marijuana: Research studies have found an association between chronic/daily use of marijuana in patients infected with hepatitis C and increased severity of fibrosis and steatosis (Abnormal accumulation of fat in the liver), the progression of the disease, and a higher level of hepatitis C RNA (Terrault, 2018). Patients should be advised to abstain from using marijuana.

Medications: Patients should not take an over-the-counter medication, dietary supplement, or herbal product unless their provider or healthcare professional determines that doing so is safe. This is especially true for patients who have advanced fibrosis or cirrhosis, and these patients may need to avoid or use lower doses of medications like acetaminophen (potentially hepatotoxic and non-steroidal anti-inflammatories (potentially nephrotoxic) (AASLDS, 2019b).

Obesity: Patients who are obese should be advised to lose weight. Obesity has been identified as a risk factor for the progression of liver fibrosis and liver damage (Garcia-Tsao, 2017).

Reinfection: An SVR does not provide immunity against reinfection with hepatitis C, either from the same genotype or the other genotypes. Patients should be instructed to contact their provider or another healthcare professional if they may have been reinfected.

Smoking: Smoking may increase fibrosis progression, and smoking cessation should be encouraged (AASLDS, 2019d).

Substance use: Patients who have a substance use disorder should be referred to a treatment program (AASLDS, 2019b). Current drug use is not a contraindication for direct-acting antiviral therapy.

Treatment adherence: Patients should be advised that non-compliance with the treatment regimen can cause treatment failure or allow a drug-resistant strain of the virus to develop.

Treatment - Adverse effects: The adverse effects of the direct-acting antivirals are mild and usually well tolerated. Patients should be instructed to contact their provider or another healthcare professional if they have any signs or symptoms that are new, unusual, severe, intolerable, or that interfere with activities of daily living. They should contact their healthcare provider or another healthcare professional if they develop any signs or symptoms indicative of liver damage.

No vaccine can prevent hepatitis C infection, and prophylactic treatment after a known or suspected exposure to hepatitis C is not recommended (AASLDS, 2019d). After acute exposure to hepatitis C, the patient should be tested for hepatitis C RNA and anti-hepatitis C antibody and, if needed, tested for hepatitis B and HIV. The hepatitis C tests should be repeated six weeks later, and treatment started if necessary (AASLDS, 2019d).